This phase II trial tests how well acalabrutinib works in treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and evaluates how treatment with acalabrutinib affects heart function. Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers at abnormal levels. This may help keep cancer cells from growing and spreading. CLL/SLL patients treated with a different BTK inhibitor called ibrutinib often experience cardiac side effects, leading to discontinuation of life-saving therapy. Treatment with acalabrutinib after discontinuing, or even before starting, treatment with ibrutinib may reverse or prevent cardiac side effects and be an effective treatment option for patients with CLL/SLL.

PRIMARY OBJECTIVE:

I. To determine cardiac magnetic resonance imaging (MRI) changes over time in patients with CLL who are intolerant to ibrutinib and switch to acalabrutinib therapy.

SECONDARY OBJECTIVES:

I. To determine the rate of recurrence of >= grade 2 adverse events (AEs) causing ibrutinib intolerance at 1 year when patients with CLL/SLL are treated with acalabrutinib.

II. To determine the response rates which include (complete response [CR], partial response [PR], PR with lymphocytosis).

III. To determine C481S/PLCG2 mutation free (defined 0 mutation bearing alleles) and clinical progression free survival at 3 years.

IV. To assess atrial fibrillation (AF) rates at 12 months post acalabrutinib transition.

EXPLORATORY OBJECTIVES:

I. To determine cardiac injury (i.e., troponin-TnT and N-terminal pro B-type natriuretic peptide [NT-proBNP]), C-reactive protein (CRP), and pro-inflammatory (ex. interleukin [IL]-6, IL-17, and tumor necrosis factor [TNF]-α, etc.) biomarkers.

II. To assess fibrosis, serum procollagen type I carboxy-terminal propeptide (PICP), galectin-3, transforming growth factor (TGF)-β1, and matrix metalloproteinases (MMPs)-2, and -7 will be collected and measured at each timepoint.

III. To determine cardiac magnetic resonance imaging (CMR) imaging changes that may be induced by acalabrutinib over time in BTK naive patients.

OUTLINE:

Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CMR, computed tomography (CT), bone marrow aspiration/biopsy, and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 6 months for up to 10 years.

Inclusion Criteria:

• Men and women >= 18 years of age

• Diagnosis of CLL/SLL meeting criteria as defined by International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2018 criteria

• CLL patients cardiac intolerant to current treatment with ibrutinib as defined by AF or other cardiac arrhythmias. Other ibrutinib-related intolerances will be excluded

• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

• Absolute neutrophil count (ANC) >= 1000/mm^3 (Independent of growth factor support at screening unless due to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia. If cytopenias are due to disease in the bone marrow any degree of cytopenias is allowed. Patients with active uncontrolled autoimmune cytopenias are excluded)

• Platelets >= 30,000/mm^3 (Independent of growth factor support at screening unless due to marrow involvement by CLL/SLL and/or disease-related immune thrombocytopenia. If cytopenias are due to disease in the bone marrow any degree of cytopenias is allowed. Patients with active uncontrolled autoimmune cytopenias are excluded)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (excepting Gilbert's syndrome) (at screening)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (at screening)

• Creatinine clearance >= 30 mL/min/1.73m^2 (at screening)

  • Using 24-hour creatinine clearance or modified Cockcroft-Gault equation

• Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib

• Willing and able to participate in all required evaluations and procedures in this study protocol

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

Exclusion Criteria:

• Prior exposure to acalabrutinib for primary cohort and prior exposure to BTK inhibitor for pilot cohort

• Presence of C481S mutation or PCLG2 mutation

• Disease progression on ibrutinib

• History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following:

  • Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study
  • Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for >= 3 years without further treatment

• Clinically significant cardiovascular disease such as prior myocarditis, congestive heart failure, prior documented myocardial infarction (i.e., not self-reported), known infiltrative cardiomyopathy (ex. cardiac sarcoidosis, cardiac amyloidosis, etc.) or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll on study

• Prior allogeneic stem cell transplantation

• Prior cardiac transplantation

• Systemic or non-cancer targeted anti-inflammatory medications (i.e., steroids)

• Contradictions to MRI: non-compatible metal implant, weight > 300 pounds (lbs.) (MRI scanner limit), severe claustrophobia, advanced or end-stage renal disease (ESRD) (contraindication to gadolinium), pregnancy, cognitive disabilities that may impair ability to comply with instructions or provide informed consent

• Has difficulty with or is unable to swallow oral medication or has significant. gastrointestinal disease that would limit absorption of oral medication

• Known history of infection with HIV or any active significant infection (e.g., bacterial, viral, or fungal) including subjects with positive cytomegalovirus [CMV] deoxyribonucleic acid [DNA] polymerase chain reaction [PCR])

• Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components

• Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)

• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)

• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening

• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited

• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists

• Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN

• Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study

• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug

• Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug

• Received a live virus vaccination within 28 days of first dose of study drug

• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)

• Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug

• Hepatitis B or C serologic status:

  • Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded
  • Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded

• Breastfeeding or pregnant

• Concurrent participation in another therapeutic clinical trial